Abstract
The number of studies investigating the human gastrointestinal tract using various single-cell profiling methods has increased substantially in the past few years. Although this increase provides a unique opportunity for the generation of the first comprehensive Human Gut Cell Atlas (HGCA), there remains a range of major challenges ahead. Above all, the ultimate success will largely depend on a structured and coordinated approach that aligns global efforts undertaken by a large number of research groups. In this Roadmap, we discuss a comprehensive forward-thinking direction for the generation of the HGCA on behalf of the Gut Biological Network of the Human Cell Atlas. Based on the consensus opinion of experts from across the globe, we outline the main requirements for the first complete HGCA by summarizing existing data sets and highlighting anatomical regions and/or tissues with limited coverage. We provide recommendations for future studies and discuss key methodologies and the importance of integrating the healthy gut atlas with related diseases and gut organoids. Importantly, we critically overview the computational tools available and provide recommendations to overcome key challenges.
Key points
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The number of studies applying single-cell sequencing methods to human intestinal tissue has been rapidly increasing, providing a unique opportunity to generate a complete map of the human intestine.
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Generation of the Human Gut Cell Atlas (HGCA) requires the coordinated efforts of groups across the globe and the integration of various data sets followed by their computational analyses.
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This article provides a roadmap for the generation of the HGCA based on the expertise and recommendations of the Gut Biological Network of the Human Cell Atlas.
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The HGCA will provide a unique and highly valuable reference map enhancing research in intestinal health and disease.
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Acknowledgements
This publication is part of the Human Cell Atlas (HCA) www.humancellatlas.org/publications. The HCA initiative receives funding from The Wellcome Trust, the UK Research and Innovation Medical Research Council, EU Horizon 2020, INSERM (HuDeCA), and the Knut and Alice Wallenberg and Erling-Persson foundations. We thank the HCA Executive Office for their support. The Gut Cell Atlas is organized by The Leona M. and Harry B. Helmsley Charitable Trust and provides funding for members in the form of project grants. M.Z. was supported by an MRC New Investigator research grant (MR/T001917/1) and a project grant from the Great Ormond Street Hospital Children’s Charity, Sparks (V4519); K.S.L. was supported by NIDDK R01DK103831, and The Helmsley Trust — G-1903-03793. S.T.M. received funding from National Institutes of Health USA R01DK115806 and P30DK034987. T.S. was supported by the Japanese Science and Technology (JST) FOREST and the Japanese Society for the Promotion of Science (JSPS) (21K18272). L.A.C. and K.T.W. were supported by The Helmsley Charitable Trust — G-1903-03793. K.T.W. was also supported by NIDDK R01DK128200. L.A.C. was supported by a Veterans Affairs Merit Award 1I01BX004366. M.K. was supported by the National Research Foundation, South Africa grant no: 129356.
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M.Z., K.R.J., M.K., S.P., Z.L., A.B., J.R.T., J.B., F.L.J., F.P., A. Ross, N.S., R.B.C., E.S.B., R.Z., B.X., K.L., S.D., S.T.M., Q.Y., S.B., M.J.A., A.D-.S., L.C., J.G., R.B., I.P., J.O-.M., S.A.T., M.P.S. and K.T.W. researched data for the article. M.Z., K.R.J., M.K., S.P., Z.L., A.B., J.R.T., J.B., F.L.J., F.P., A. Ross, G.M., N.S., T.S., A.M., R.B.C., E.S.B., R.Z., B.X., K.L., S.D., S.T.M., Q.Y., S.B., M.J.A., A.D-.S., L.C., J.G., R.B., I.P., J.O-.M., G.E.B., A.H., S.A.T., A. Regev, R.J.X., M.P.S. and K.T.W. contributed substantially to discussion of the content. M.Z., K.R.J., M.K., S.P., Z.L., A.B., J.R.T., J.B., F.L.J., F.P., A. Ross, N.S., T.S., R.B.C., E.S.B., R.Z., B.X., K.L., S.D., S.T.M., Q.Y., S.B., M.J.A., A.D-.S., L.C., J.G., R.B., I.P., G.E.B., S.A.T., M.P.S. and K.T.W. wrote the article. M.Z., K.R.J., M.K., S.P., Z.L., A.B., J.R.T., J.B., F.L.J., F.P., A. Ross, G.M., T.S., A.M., R.B.C., E.S.B., R.Z., B.X., K.L., S.D., S.T.M., Q.Y., S.B., M.J.A., A.D-.S., L.C., J.G., R.B., I.P., J.O-.M., G.E.B., A.H., S.A.T., A. Regev, R.J.X., A.S., M.P.S. and K.T.W reviewed and/or edited the manuscript before submission.
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In the past 3 years, S.A.T. has consulted or been a member of scientific advisory boards at Roche, Genentech, Biogen, GlaxoSmithKline, Qiagen and ForeSite Labs and is an equity holder of Transition Bio. G.M. has received grant funding from Boehringer Ingelheim. A. Regev is a co-founder and equity holder of Celsius Therapeutics, an equity holder in Immunitas, and was a SAB member of ThermoFisher Scientific, Syros Pharmaceuticals, Neogene Therapeutics and Asimov until 31 July 2020. Since 1 August 2020, A. Regev has been an employee of Genentech and has equity in Roche. A. Regev is an inventor on patents and patent applications filed at the Broad Institute related to single-cell genomics. The remaining authors declare no competing interests.
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Related links
Gut Cell Atlas: https://www.gutcellatlas.org
HCA Gut Bionetwork: https://www.humancellatlas.org/biological-networks/
Helmsley Charitable Trust (Gut Cell Atlas): https://helmsleytrust.org/our-focus-areas/crohns-disease/crohns-disease-therapeutics/gut-cell-atlas/
HuBMAP Portal: https://portal.hubmapconsortium.org/
Human BioMolecular Atlas Program: https://hubmapconsortium.github.io/ccf/pages/ccf-3d-reference-library.html
Single Cell Expression Atlas: https://www.ebi.ac.uk/gxa/sc/home
Single Cell Portal: https://singlecell.broadinstitute.org/single_cell
Tabula Sapiens: https://tabula-sapiens-portal.ds.czbiohub.org
The Human Cell Atlas – Metadata: https://data.humancellatlas.org/metadata
University of California at Santa Cruz (UCSC) Cell Browser: https://cells.ucsc.edu
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Zilbauer, M., James, K.R., Kaur, M. et al. A Roadmap for the Human Gut Cell Atlas. Nat Rev Gastroenterol Hepatol 20, 597–614 (2023). https://doi.org/10.1038/s41575-023-00784-1
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DOI: https://doi.org/10.1038/s41575-023-00784-1
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